Method for the treatment or prevention of lower urinary tract symptoms

ABSTRACT

This invention concerns a method for treatment or prevention of lower urinary tract symptoms with or without pelvic pain in an individual, said method comprising administering to the individual an effective amount of a selective estrogen receptor modulator, or an isomer, isomer mixture or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/832,649, filed on Aug. 21, 2015, which is a continuation of U.S.patent application Ser. No. 14/597,453, filed on Jan. 15, 2015, which isa continuation of U.S. patent application Ser. No. 13/970,026, filed onAug. 19, 2013, which is a continuation of U.S. patent application Ser.No. 12/856,738, filed on Aug. 16, 2010, which is a continuation of U.S.patent application Ser. No. 10/454,823, filed on Jun. 5, 2003, all ofwhich are incorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to a method for treatment or prevention of lowerurinary tract symptoms with or without pelvic pain in an individual,said method comprising administering to the individual an effectiveamount of a selective estrogen receptor modulator (SERM).

BACKGROUND OF THE INVENTION

The publications and other materials used herein to illuminate thebackground of the invention, and in particular, cases to provideadditional details respecting the practice, are incorporated byreference.

Lower Urinary Tract Symptoms (LUTS)

Typical clinical symptoms included in this group are hesitance, poorurinary stream, terminal drippling and incomplete bladder emptying. Themain functional cause of LUTS is urethral sphincter dysfunction. Theurethral sphincter consists of a voluntary (striated) sphincter(rhabdosphincter) and an involuntary (smooth) sphincter. The distal partof the male rhabdosphincter surrounds the membranous part of the urethraand is called external sphincter. The upper or prostatic part of therhabdosphincter is layered out over the anterior and lateral aspects ofthe prostate and embedded in the prostatic stroma in men. The urethralsmooth muscle is located at the bladder neck and prostatic urethra inmen. Lowering of resistance of the smooth and striated sphincter,associated with coordinated detrusor contraction determines completemicturition. In urethral sphincter dysfunction an increased intraluminalbladder pressure is needed to empty the bladder. In the initial stages,there is no reduction in the flow rate because the maximum micturitionpressure compensates for the increased outflow resistance. The reductionof the flow rate developing in more advanced clinical stages of urethraldysfunction correlates poorly with the degree of prostatic enlargement.

Three different clinical outcomes have been described: 1) bladder neckdyssynergia, 2) external sphincter pseudodyssynergia and 3) Hinmansyndrome. They have all been defined as detrusor urethral sphincterdyssynergia.

Bladder neck dyssynergia is defined as the inability of the bladder neckto open properly and assume a funnel shape in the presence of a normaldetrusor contraction. Video imaging techniques allow the diagnosis ofthe smooth sphincter dyssynergia. The bladder neck dyssynergia is alife-long condition, and virtually never occurs in the female. The causeof the bladder neck dyssynergia is unknown.

During the normal micturition cycle, an increase in external sphincterelectromyographic activity accompanies bladder filling (continencereflex). This is followed by relaxation of rhabdosphincter and thepelvic floor muscles, which begins before or at the beginning of thedetrusor contraction and persists throughout the contraction.Rhabdosphincter dyssynergia is defined as an inappropriate increase instriated urethral muscle (external urethral sphincter) activity during adetrusor contraction and is a well recognized cause of voidingdysfunction in patients with upper neurone lesions. Thisovercompensation owing to the loss of supraspinal influences is done tocounteract the elevated bladder pressure caused by uninhibited detrusorcontraction (an exaggerated continence reflex). In external sphincterpseudodyssynergia, incoordination between the bladder and urethralsphincter is not due to a neurological lesion but is secondary to adysfunction resulting in an increased tone of the external sphincter andthe pelvic floor muscles. Pseudodyssynergia is determined byintermittent increase in sphincter EMG and/or intermittent narrowing ofthe urethra at this site.

Urodynamic investigations in children with an abnormal voiding patternhave shown dyssynergia between the detrusor and striated urethralsphincter in the absence of neurological disease (non-neurogenicneurogenic bladder or the Hinman syndrome). This appears to result fromunintentional, habitual contractions of the striated urethral sphincterin response to involuntary bladder contraction to prevent urinaryincontinence. This dyssynergia probably may at least partly represent alearned habit. The relationship between the Hinman syndrome and theexternal sphincter pseudodyssynergia is not known.

Patients with urethral sphincter dysfunction may develop secondarydetrusor instability with irritative symptoms of frequency, urgency andnocturia.

LUTS may be associated with chronic pelvic pain. The article written byOliver W Hakenberg and Manfred P Wirth (Urol Int 2002:68:138-143),concerns chronic pelvic pain syndrome (CPPS) in men. This is defined asa condition of pelvic pain of more than 6 months duration. Certainconditions causing CPPS are mentioned, namely abacterial prostatitis,stress prostatitis, prostatodynia, urethral syndrome, trigonitis andorchialgia. Interstitial cystitis in men or women will also typicallyresult in pelvic pain. A primary difficulty noted in patients with CPPSis the inability to voluntarily relax the external sphincter and thepelvic floor muscles. This will result in the emergency of LUTS anddyssynergic voiding.

On the basis of the findings in experimental animals (Streng:Hormone-related reversible urinary rhabdosphincter disorder in malelaboratory rodents—possible clinical implications. Academicdissertation, University of Turku, 2002), we suggest that the increasedratio of estrogen to androgen concentration (relative over aromatizationof androgens) in the organism plays a role in the development of theurethral sphincter dysfunction in men. In male animals chronicallytreated with estrogen bladder outlet obstruction develops with completeurinary retention and hypertrophy of the bladder wall. Neonatallyestrogenized animals have a lower voided urine volume and decreasedratio of urinary flow rate—to—bladder pressure, which are consistentwith infravesical obstruction. These urodynamic changes of theneonatally estrogenized animals are reversed after the treatment ofaromatase inhibitor in adulthood. The urethral smooth and striatedsphincters and neurones innervating them show androgen and estrogenreceptors suggesting that they are the potential target of androgens andestrogen actions. The prostate of these animals have reduced size andshow signs of inflammation.

U.S. Pat. No. 5,972,921 describes a method for the treatment of detrusorurethral sphincter dyssynergia in men by administering an aromataseinhibitor to the patient. Said patent gives a summary of the clinicalsymptoms of male functional detrusor urethral sphincter dyssynergia andits treatments taking into account especially the possible hormonalbackground of the symptoms. Aromatase inhibitors, when studied in menwith urinary symptoms (A Radlmaier et al., The Prostate 29:199-208(1996); J C Gingell et al., The Journal of Urology, vol. 154,399-401,August 1995), increase the concentrations of testosterone. This causesan increase in the size of prostate and on the other hand may worsen thestatic obstruction caused by the enlarged prostate and consequently thesymptoms. Therefore, other mechanisms of action are desirable. SERMs,which act as antiestrogens in the urinary tract, decrease thedetrimental effect of natural estrogens without stimulating the prostatesize. They can be considered as potentially beneficial compounds intreating the symptoms and functional causes of LUTS.

Selective Estrogen Receptor Modulators

“SERMs” (selective estrogen receptor modulators) have both estrogen-likeand antiestrogenic properties (Kauffman & Bryant, Drug News Perspect8:531-539, 1995). The effects may be tissue-specific as in the case oftamoxifen and toremifene which have estrogen-like effects in the bone,partial estrogen-like effect in the uterus and liver, and pureantiestrogenic effect in breast cancer. Raloxifene and droloxifen aresimilar to tamoxifen and toremifene, except that their antiestrogenicproperties dominate. They are known to decrease total and LDLcholesterol, thus diminishing the risk of cardiovascular diseases, andthey may prevent osteoporosis and inhibit breast cancer growth inpostmenopausal women. There are also almost pure antiestrogens underdevelopment. They are mainly aimed at the treatment of breast cancer(Wakeling & Bowler, J Steroid Biochem 30:1-6, 1988).

A review of investigated and/or marketed SERM compounds is published inV Craig Jordan, J Medicinal Chemistry (2003):46, No. 7.

SUMMARY OF THE INVENTION

The inventors of the present invention have surprisingly found thatcompounds belonging to the group of selective estrogen receptormodulators have beneficial effects on urodynamic parameters in animalstudies. Therefore, the inventors suggest that this class of compoundsmay be useful for treating or preventing LUTS caused by urethralsphincter dysfunction.

Thus, this invention concerns a method for treatment or prevention oflower urinary tract symptoms with or without pelvic pain in anindividual, said method comprising administering to the individual aneffective amount of a selective estrogen receptor modulator, or anisomer, isomer mixture or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a typical micturition cycle (a=bladder pressure; b=flowrate).

FIG. 2 shows the maximal bladder pressure for non-estrogenized rats andfor neoDES rats with and without administration of test compounds.

FIG. 3 shows the average bladder pressure for non-estrogenized rats andfor neoDES rats with and without administration of test compounds.

FIG. 4 shows the maximal flow rate for non-estrogenized rats and forneoDES rats with and without administration of test compounds.

FIG. 5 shows the average flow rate for non-estrogenized rats and forneoDES rats with and without administration of test compounds.

FIG. 6 shows the micturition time for non-estrogenized rats and forneoDES rats with and without administration of test compounds.

FIG. 7 shows the amount of residual urine for non-estrogenized rats andfor neoDES rats with and without administration of test compounds.

FIG. 8 shows the bladder capacity for non-estrogenized rats and forneoDES rats with and without administration of test compounds.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “individual” relates particularly to humans, but it shall alsobe considered to include animals.

The term “lower urinary tract symptoms” relates to symptoms in male aswell as in female individuals. For male individuals, a particularlyimportant class of such symptoms is detrusor urethral sphincterdyssynergia, but the term is not restricted hereto. Any kind of symptomsin the lower urinary tract in male individuals shall be covered by theterm. Thus, in this invention the term “lower urinary tract symptoms”shall also be understood to include abacterial prostatitis, stressprostatitis, trigonitis and orchialgia in male individuals, andinterstitial cystitis in male or female individuals. For femaleindividuals, this term further include bladder instability andmicturition urgency.

The term “pelvic pain” shall here be understood to include symptomsrelated to abacterial prostatitis, stress prostatitis, prostatodynia,urethral syndromes, trigonitis or orchialgia in a male individual.Furthermore, the term includes interstitial cystitis either in male orfemale individuals.

The wording “selective estrogen receptor modulator” and any specificcompound belonging to this group shall be understood to cover anygeometric isomer, any stereoisomer, racemate or other mixture of isomersof the compound. Furthermore, pharmaceutically acceptable salts andother derivatives such as esters are also included.

Suitable selective estrogen receptor modulators (or SERMs) for use inthis invention are, for example, the compounds disclosed in V CraigJordan (2003).

Thus, examples of suitable SERM compounds for use in the presentinvention are triphenylalkene or triphenylalkane compounds such ascompounds disclosed in WO 01/36360, U.S. Pat. Nos. 4,996,225, 4,696,949,5,750,576, WO 99/42427 and the toremifene metabolites disclosed in LKangas, Cancer Chemother Pharmacol (1990)27:8-12. As examples ofspecific drugs disclosed in the aforementioned references can bementioned toremifene, fispemifene and ospemifene. Tamoxifen and itsderivatives such as 4-hydroxytamoxifen, alpha-hydroxytamoxifen,N-desmethyltamoxifen, N,N-didesmethyltamoxifen, deaminotamoxifen, anddroloxifene and iodoxifene also examples of suitable SERMs oftriphenylalkene structure.

Other preferable examples of SERM compounds are compounds ofbenzothiophene structure, such as raloxifene and its analogues(described for example in EP 584952, U.S. Pat. Nos. 4,133,814,4,418,068) and arzoxifene.

As further examples of suitable SERMs can be mentioned EM652, EM800,EM776, EM651, EM312, ICI 182780, ERA-923, zindoxifene and deacetylatedzindoxifene, ZK119010, TSE-4247, lasoxifene and its analogues,particularly those disclosed in EP 802910, nafoxidine, basedoxifene,GW5638, GW7604, compound no. 32 disclosed in Jordan (2003), ICI 164384,RU 58668, RU 39411 and EM 319.

The aforementioned specific SERMs or classes of SERMs are examples only,and other SERMs may be suitable for use in this invention as well.

SERMs with no or weak estrogenic effect may be suitable for use,particularly in male individuals. A classical method to determine theestrogenic profile of a compound is to evaluate estrogenic effect inimmature mouse or rat uterus (Terenius L, Acta Endocrinol 66:431-447,1971). The animals are exposed for 3 days to the compounds to beinvestigated at the age of 18 days. On the fourth day the animals aresacrificed and body weight and uterine weight is recorded. Estrogensincrease the size and weight of the uterus (uterotropic effect) whileantiestrogens inhibit this action. The results are given as percent ofestrogen stimulation (100% with estradiol). In our tests, we used a highdose level, i.e. 10-50 mg/kg. Compounds causing an uterotropic effect≤40% are for this purpose classified as weak estrogenic compounds,compounds causing an uterotropic effect ≥70% are classified as strongestrogenic compounds and compounds in-between, an uterotropic effect of41-69% are classified as moderate estrogenic agents.

As specific examples of particularly useful SERMs can be mentionedcertain compounds of those disclosed in WO 01/36360 (incorporated hereinby reference), namely

-   (Z)-2-[3-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol-   (Z)-2-{2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol    (also known under the generic name fispemifene)-   (Z)-{2-[3-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethyl}dimethylamine-   (E)-3-{4-Chloro-1-[4-(2-hydroxyethoxy)phenyl]-2-phenyl-but-1-enyl}-phenol-   (E)-3-{4-Chloro-1-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-1-enyl}-phenol,    and-   (Z)-3    (Z)-3-{4-Chloro-1-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-1-enyl}-phenol.

The aforementioned six compounds are all classified as weak estrogenicSERMs.

For the purpose of this invention, the SERM or its isomer, isomermixture or their pharmaceutically acceptable salts can be administeredby various routes. The suitable administration forms include, forexample, oral formulations; parenteral injections including intravenous,intramuscular, intradermal and subcutaneous injections; and transdermalor rectal formulations. Suitable oral formulations include e.g.conventional or slow-release tablets and gelatine capsules.

The required dosage of the SERM compounds will vary with the particularcondition being treated, the severity of the condition, the duration ofthe treatment, the administration route and the specific compound beingemployed. For example, fispemifene can be administered perorallypreferentially once daily. The daily dose may be 5-150 mg, preferably20-100 mg. Fispemifene can be given as tablets or other formulationslike gelatine capsules alone or mixed in any clinically acceptablenon-active ingredients which are used in the pharmaceutical industry.

The invention will be illuminated by the following non-restrictiveExperimental Section.

EXPERIMENTAL SECTION

Methods and Materials

Tested Drugs:

We studied the effects of two SERMs, namely fispemifene, which also isknown under the code HM-101, and raloxifene on voiding in control aswell as in developmentally estrogenized male rats. As vehicle was usedpolyethylene glycol (PEG).

Animals:

Male rats were supplied by The Central Animal Laboratory of theUniversity of Turku, Finland. Their mean age was 222 days (SD 48.4). Thenumber of the non-estrogenized rats was 50 and the number ofdevelopmentally estrogenized rats was 29. The rats were maintained understandard laboratory conditions at 12:12 light/dark cycle and they gotsoyfree pelleted food (SDS, Witham, Essex, UK) with free access. Theyhad also free access to tap water.

The estrogenized rats (neoDES) were developed as follows: Male Noblerats were treated neonatally with estrogen (10 μg of diethylstilbestrol(DES)) in rap seed oil (10 g/40 μl) s.c. on days 1-5 of postnatal life.After the treatment with diethylstilbestrol, the neoDES rats were leftto grow for 4-5 months before treatment with study drugs.

Dosing and Weighing:

The dosing volume was 0.2 ml solutions/50 g body weight and the doselevel of fispemifene or raloxifene 1 and/or 10 mg/kg body weight. Thedose was given once a day for six weeks. The rats were weighed for thefirst time on the same day, as the treatments began. Afterwards theanimals were weighed once a week. This was carried out to ensure theright dosing to rats.

Study Design for Urodynamic Studies:

There were eight groups of adult male rats. The anaesthetized rats(non-estrogenized or neonatally estrogenized) were treated orally withfispemifene or raloxifene using doses of 1 and/or 10 mg/kg body weight.

The following animal codes are used in the study:

Treatment of Non-Estrogenized Rats:

Control rats (only with vehicle treatment) Co Rats treated withfispemifene, 1 mg/kg dose HMCo1 Rats treated with fispemifene, 10 mg/kgdose HMCo10 Rats treated with raloxifene, 1 mg/kg dose RalCo1 Ratstreated with raloxifene, 10 mg/kg dose RalCo10

Treatment of Neonatally Estrogenized Rats:

Control rats (neoDES) (only with vehicle treatment) neoDES Rats treatedwith fispemifene, 10 mg/kg dose HMDES10 Rats treated with raloxifene, 10mg/kg dose RalDES10

The above codes are used in the tables and figures.

Measurements and Apparatus:

The rats were anesthetized with chloral hydrate (0.9 g/kg, SigmaChemical Co. St. Luis. Mo. 63178, USA) for a basic anaesthetic, and i.v.injection of urethane (0.32 g/kg, Sigma Chemical Co. St. Luis. Mo.63178, USA) was used to maintain anesthesia for urodynamic measurements.The body temperature was kept constant at +36-38° C. by athermostatically controlled animal blanket and if needed, with a heatinglamp. The bladder and the distal part of urethra were exposed with amidline incision of the lower abdomen. In transvesical cystometry a 20 Gi.v. cannula was inserted through the bladder apex into the lumen. Thecannula was connected to an infusion pump and to a pressure transducer.The whole system was filled with saline. Measurements were made at theinfusion rate of 0.23 ml/min. An ultrasonic flow probe was used formeasurement of the flow rate from the distal part of urethra. The flowprobe was connected to a flow meter, with sampling rate of 100 Hz. Atthe same time with the measurements of transvesical cystometry and flowrate, the electrical activity of the striated urethral sphincter(rhabdosphincter) was measured extracellularly with suction electrode.The electrode was attached on anterior surface of the muscle by suction(provided by a flow of tap water). The suction electrode and pressuretransducer were connected to an amplifier. Low frequency AC coupling(0.8 Hz) was used in electrical activity measurement. The reference andground electrodes were placed on the edge of the wound so that ECGsignal was not observable. The tissues were kept moist duringmeasurements with warm (+37° C.) saline. The pressure and flow metersignals were transferred to the Biopac-system. The Biopac-system wasconnected to a personal computer. Continuous recording was made with AcqKnowledge 3.5.3 program with sample rate of 400 Hz.

The setup of the apparatus for use in this method is disclosed in U.S.Pat. No. 5,972,921 (column 9-10, FIG. 3).

Three representative voidings were chosen for further analysis from eachrat. Intraluminal pressure high frequency oscillations (IPHFOs) ofbladder pressure are characteristic in male rodent micturition duringthe second phase, during which also the urine flow occurs. The maximumand mean bladder pressures were calculated from the pressureoscillations seen in pressure wave. The maximum value was measured fromthe highest peak and the mean value from all IPHFOs during the secondphase of micturition. The maximum flow rate value was measured from thehighest flow rate peak and the mean flow rate value from all flow peaksduring the second phase of micturition. The duration of the micturitionand the volume of the residual urine were measured.

FIG. 1 illustrates one typical micturition cycle showing bladderpressure wave (a) and flow rate wave (b), and the method for calculationof the urodynamic parameters. The measurement of the maximal bladderpressure, flow rate, and micturition time are shown in the figure.Parameters of mean bladder pressure and-flow rate are measured asaverage from all the bladder pressure and flow rate peaks, respectively.

Statistics

Continuous recording was made by Acq Knowledge 3.5.3 program (MP100Manager Ver. 3.5.3, Copyright © 1992-95 BIOPAC Systems Inc.). Furthernumerical data were carried out with Excel 2000 (Microsoft Corporation,Redmond, Wash., USA), and the statistical analysis with Statistica forWindows 5.1 (Stat Soft, Inc., Tulsa, Okla., USA). Statistical analysiswas carried out with ANOVA and the post hoc tests with HSD test. IfLevene's test for variances shows significant differences (p<0.05)between the treatment groups, Kruskall-Wallis test was be used, andMann-Whitney U test was used as a post hoc test.

Results

Bladder Pressure

There were no significant differences in the bladder pressures (maximaland mean) between the groups (Tables 1 and 2). Because neoDES treatmentdid not influence on the bladder pressure, it is not expected that SERMswould influence on it either.

TABLE 1 Maximal bladder pressure (MBP) (measured from highest bladderpressure oscillation). M = Mann-Whitney U test. P-value Co compared toMBP neoDES and Co rat treatments, Animal group and Mean and neoDEScompared to treatment (mmHg) SD HMDES10 and RalDES10 Co, (n = 10) 35.52.73 HMCo1, (n = 10) 38.2 6.06 0.13 (M) HMCo10, (n = 10) 35.1 2.01 0.36(M) RalCo1, (n = 10) 36.9 6.12 0.71 (M) RalCo10, (n = 10) 39.4 8.49 0.29(M) neoDES, (n = 9) 34.4 6.43 0.22 (M) HMDES10, (n = 10) 38.2 7.97 0.32(M) RalDES10, (n = 8) 35.9 8.41 0.92 (M)

TABLE 2 Mean bladder pressure (MeBP) (measured from all bladder pressureoscillations). A = One Way ANOVA and Tukey HSD test; M = Mann-Whitney Utest. P-value Co compared to MeBP neoDES and Co rat treatments, Animalgroup and Mean and neoDES compared to treatment (mmHg) SD HMDES10 andRalDES10 Co, (n = 10) 26.0 2.14 HMCo1, (n = 10) 25.8 3.77 0.99 (A)HMCo10, (n = 10) 24.4 2.89 0.85 (A) RalCo1, (n = 10) 26.7 3.73 0.99 (A)RalCo10, (n = 10) 25.8 4.12 0.99 (A) neoDES, (n = 9) 24.8 3.69 0.97 (M)HMDES10, (n = 8) 25.6 5.67 1.00 (M) RalDES10, (n = 8) 24.1 3.16 0.44 (M)

The maximal and average bladder pressures are also shown in FIGS. 2 and3.

Flow Rate

Decreased urine flow rate is a definite sign of urination problems.NeoDES treatment decreased the flow rate and SERMs normalized itindicating a positive effect on urodynamics. Treatment with fispemifeneor raloxifene increased both the maximal (Table 3) and mean (Table 4)flow rate in non- and neonatally estrogenized rats with dose of 10mg/kg. No differences were seen with dose of 1 mg/kg in non-estrogenizedrats. Neonatally estrogenized rats received only 10 mg/kg of drugtreatment. Neonatally estrogenized rats showed lower flow rates thannon-estrogenized rats.

TABLE 3 Maximal flow rate (MFR) (measured from highest flow rate peak).A = One Way ANOVA and Tukey HSD test; M = Mann-Whitney U test. P-valueCo compared to MFR neoDES and Co rat treatments, Animal group and Meanand neoDES compared to treatment (ml/min) SD HMDES10 and RalDES10 Co, (n= 10) 34.0 11.95 HMCo1, (n = 10) 40.9 20.90 0.90 (A) HMCo10, (n = 10)55.8 20.13 0.053 (A) RalCo1, (n = 10) 40.1 13.32 0.93 (A) RalCo10, (n =10) 67.1 18.39 0.001 (A) neoDES, (n = 9) 24.8 6.80 0.07 (M) HMDES10, (n= 10) 40.9 15.14 0.007 (M) RalDES10, (n = 8) 45.9 20.66 0.03 (M)

TABLE 4 Mean flow rate (MeFR) (measured from all flow rate peaks). M =Mann- Whitney U test. P-value Co compared to MeFR neoDES and Co rattreatments, Animal group and Mean and neoDES compared to treatment(ml/min) SD HMDES10 and RalDES10 Co, (n = 10) 4.9 1.64 HMCo1, (n = 10)6.5 3.63 0.50 (M) HMCo10, (n = 10) 8.4 4.38 0.03 (M) RalCo1, (n = 10)5.8 1.95 0.26 (M) RalCo10, (n = 10) 8.3 2.81 0.008 (M) neoDES, (n = 9)3.3 1.19 0.03 (M) HMDES10, (n = 10) 5.8 2.12 0.009 (M) RalDES10, (n = 8)6.3 3.72 0.02 (M)

The maximal and mean flow rates are also shown in FIGS. 4 and 5.

Micturition Time

Micturition time was significantly prolonged in neonatally estrogenizedrats (Table 5). This is well understandable, because the urine flow ratewas decreased. Treatments with HM-101 or raloxifene did not shorten themicturition time in non-estrogenized rats. In neonatally estrogenizedrats the treatments shortened the micturition time. Although the effectdid not quite reach the statistical significance, the effect can beconsidered beneficial.

TABLE 5 Micturition time (MT; the time from the first flow peak to lastone). M = Mann-Whitney U test. P-value Co compared to MT neoDES and Corat Animal group and Mean treatments, and neoDES compared to treatment(sec) SD HMDES10 and RalDES10 Co, (n = 10) 7.8 2.10 HMCo1, (n = 10) 6.61.75 0.29 (M) HMCo10, (n = 10) 6.6 2.93 0.20 (M) RalCo1, (n = 10) 7.42.27 0.45 (M) RalCo10, (n = 10) 7.5 1.62 0.82 (M) neoDES, (n = 9) 19.16.97 0.001 (M) HMDES10, (n = 10) 13.1 7.16 0.07 (M) RalDES10, (n = 8)13.4 7.03 0.054 (M)

The micturition time is also shown in FIG. 6.

Residual Urine

The amount of residual urine was increased significantly in neonatallyestrogenized rats indicating that the bladder was not completely emptyafter urination. Residual urine leads to increased urination frequencyand is also a risk factor of lower urinary tract infections. Thetreatment with fispemifene (10 mg/kg) did reduce the amount of residualurine both in non- and neonatally estrogenized rats. This result is verypromising and indicates improved functional activity of the bladder.Raloxifene (10 mg/kg) reduced the amount of residual urine almostsignificantly in non-estrogenized, and significantly in neonatallyestrogenized rats (Table 6).

TABLE 6 Residual urine (RU). M = Mann-Whitney U test. P-value Cocompared to RU neoDES and Co rat Animal group and Mean treatments, andneoDES compared to treatment (ml) SD HMDES10 and RalDES10 Co, (n = 10)0.58 0.192 HMCo10, (n = 10) 0.35 0.182 0.02 (M) RalCo10, (n = 10) 0.420.139 0.07 (M) neoDES, (n = 9) 1.31 0.620 0.009 (M) HMDES10, (n = 10)0.63 0.507 0.04 (M) RalDES10, (n = 8) 0.64 0.202 0.02 (M)

The residual urine is also shown in FIG. 7.

Bladder Capacity

Bladder capacity was increased significantly in neonatally estrogenizedrats. Although the increased bladder capacity can be consideredbeneficial as such, the increase in neoDES rats indicates abnormalrelaxation of bladder wall muscles and thus damage of the bladder (dueto residual urine and slow urine flow). The bladder tries to compensatethe increased need of bladder volume. However, in such conditions thebladder wall looses its strength. Treatment with fispemifene (10 mg/kg)reduced significantly the bladder capacity in neonatally estrogenizedrats, and raloxifene almost significantly indicating that the bladderwall has retained its normal strength and function. This effect can beconsidered very beneficial. No effects were seen in non-estrogenizedrats (Table 7). This is expected, as the bladder in these animals is notdamaged.

TABLE 7 Bladder capacity (BC). M = Mann-Whitney U test. P-value Cocompared to BC neoDES and Co rat Animal group and Mean treatments, andneoDES compared to treatment (ml) SD HMDES10 and RalDES10 Co, (n = 10)0.88 0.210 HMCo10, (n = 10) 0.79 0.191 0.41 (M) RalCo10, (n = 10) 0.810.206 0.45 (M) neoDES, (n = 9) 1.678 0.468 0.001 (M) HMDES10, (n = 10)1.21 0.486 0.04 (M) RalDES10, (n = 8) 1.22 0.285 0.054 (M)

The bladder capacity is also illustrated in FIG. 8.

Discussion and Conclusions

Treatments with SERMs (fispemifene or raloxifene) had similar effects innon- and neonatally estrogenized rats. They had increased maximum andmean flow rates. Duration of micturition consisting of multiple voidingsin neonatally estrogenized rats was shortened, while no differences wereseen in bladder pressures between the groups. Amount of residual urinewas reduced both in non- and neonatally estrogenized rats, whichindicates improvement of bladder function even in the non-estrogenizedrats as well as the increase in flow rates does. It is known thatestrogenization of the rodents increases the bladder capacity. This wasevident also in present study. The treatments with these SERMs decreasedthe bladder capacity in neonatally estrogenized rats. Thus the studiedSERMs had antiestrogen function on bladder capacity. The rhabdosphincterfunction was improved in both non- and neonatally estrogenized rats, butthe EMG changes were not statistically significant.

Fispemifene and raloxifene reversed the estrogen-related alterations inflow rates, micturition time, and bladder capacity (fispemifene even innon-estrogenized rats).

It will be appreciated that the methods of the present invention can beincorporated in the form of a variety of embodiments, only a few ofwhich are disclosed herein. It will be apparent for the expert skilledin the field that other embodiments exist and do not depart from thespirit of the invention. Thus, the described embodiments areillustrative and should not be construed as restrictive.

The invention claimed is:
 1. A method for treatment of lower urinarytract symptoms with or without pelvic pain in a male individual, saidmethod comprising administering to the individual an effective amount of(Z)-2-{2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol(fispemifene), or a pharmaceutically acceptable salt thereof, whereinthe lower urinary tract symptoms comprise abacterial prostatitis.
 2. Themethod according to claim 1, wherein the method comprises administeringto the individual an effective amount of fispemifene.